Visceral Leishmaniasis (VL) is a fatal disease of the internal organs caused by the eukaryotic parasite Leishmania. Control of VL would best be achieved through vaccination. However, this has proven to be difficult partly because the correlates of protective immunity are not fully understood. In contrast, protective immunity against non-fatal cutaneous Leishmaniasis (CL) is well defined and mediated by rapidly recruited, IFNg-producing, Ly6C+CD4+ T cells at the dermal challenge site. Protection against CL is best achieved by prior infection or live vaccination with L. major, termed leishmanization. A long-standing question is whether prior CL or leishmanization can protect against VL. Employing an intra-dermal challenge model in mice, we found that cutaneous infection with Leishmania major provides heterologous protection against visceral infection with Leishmania infantum. Protection was associated with a robust CD4+ T cell response at the dermal challenge site and in the viscera. In-vivo labeling of circulating cells revealed that increased frequencies of IFNg+CD4+ T cells at sites of infection is due to recruitment or retention of cells in the tissue, rather than increased numbers of cells trapped in the vasculature. Shortly after challenge IFNg producing cells were highly enriched for Ly6C+T-bet+ cells in the viscera. Surprisingly, this heterologous immunity was superior to homologous immunity mediated by prior infection with L. infantum. Our observations demonstrate a common mechanism of protection against different clinical forms of leishmaniasis. The efficacy of leishmanization against experimental VL may warrant the introduction of the practice in VL endemic areas or during outbreaks of disease. As most currently licensed vaccines work by eliciting humoral responses that can be maintained for long periods even in the absence of persisting antigen, an anti-Leishmania vaccine that can rely on antibodies to inhibit the infectious process in the mammalian host might overcome one of the main barriers to the development of an effective T cell based vaccine. We have explored the possibility that antibodies targeting the infective, metacyclic promastigotes inoculated by the sand fly vector might be inhibitory to the earliest stages of infection in the mammalian host. We have data to show that passive immunization of mice with a monoclonal antibody directed against the common phosphoglycan chains of lipophosphoglycan (LPG) and proteophosphoglycan (PPG), representing the major surface and secreted molecules of Leishmania promastigotes, conferred complete protection against cutaneous leishmaniasis due to Leishmania major transmitted by infected sand flies. Current studies are designed to extend this vaccination strategy to the visceral form of disease; specifically, to demonstrate the ability of a B-cell based vaccine targeting the LPG/PPG expressed by the infectious stage of L. donovani to protect hamsters against VL transmitted by infected sand flies. Innate responses associated with infection involving cutaneous and visceral strains of leishmaniasis are being studied in mouse models of CL and VL. Following transmission to the skin by the bite of an infected sand fly or by needle, L. major produces localized cutaneous lesions while L. infantum disseminates to the liver and spleen while producing little or no pathology in the skin. The mechanisms by which L. infantum disseminates and does not induce skin pathology are still unknown. Comparing the infected cells in the skin at 18h following L.m or L.i. infection, we observed that both parasites were mainly found within neutrophils, where they remained viable. At day 3, they transitioned into dermal macrophages during L.i. infection while monocyte-derived DCs and conventional DCs harbored L.m. parasites. In vitro infection demonstrated that L.i. parasites induced bone marrow inflammatory monocytes to differentiate into macrophages whereas L.m. favoured the differentiation into Tip-DCs. Further stuies are in progress to confirm that Leishmania skin tropism is governed by the differential maturation of inflammatory monocytes early during the infection. Mouse models are also being used to study non-healing forms of cutaneous disease. Infection of C57BL/6 mice with the L. major Seidman strain (LmSd) isolated from a patient with chronic cutaneous lesions, despite eliciting a strong Th1 response, results in a non-healing lesion, poor parasite clearance, and complete destruction of the ear dermis. We show that infection with LmSd elicited early upregulation of IL-1b producing dermal cells driving prominent neutrophils recruitment to the site of infection in the skin. Mice genetically deficient in the inflammasome components Nlrp3, ASC, and caspase-1/11, or lacking either IL-1b or IL-1 receptor signaling, developed healing lesions and cleared LmSd parasites from the site. Resistance to LmSd infection in IL-1R-/- and Nlrp3-/- mice was associated with a stronger antigen-specific Th1 response. The possibility that IL-1b might be acting through the recruitment of neutrophils to locally suppress immunity was supported by the healing phenotype observed in neutropenic Genista mice. Secretion of mature IL-1b by LmSd infected macrophages in vitro was dependent on activation of the Nlrp3 inflammasome and caspase-1. These data reveal that Nlrp3 inflammasome dependent IL-1b mediating neutrophil recruitment to the site, plays a crucial role in the development of a severe, non-healing form of cutaneous leishmaniasis in conventionally resistant mice. The mechanisms underlying the failure to control the growth and systemic spread of Leishmania parasites in human visceral leishmaniasis (VL) are not well understood. Immunoregulatory networks are established to prevent tissue damage caused by inflammation. Although these immune checkpoints preserve tissue function, they allow pathogens and tumors to persist, and even expand. We examined the potential of modulating glucocorticoid-induced TNF receptor-related protein (GITR) on T cells to improve anti-parasitic immunity in blood and spleen tissue from visceral leishmaniasis (VL) patients infected with Leishmania donovani. We found little effect on parasite growth or parasite-specific IFNg production. However, this treatment reversed the improved anti-parasitic immunity achieved by IL-10 blockade. Further investigations using an experimental VL model caused by infection of C57BL/6 mice with L. donovani revealed that that this negative effect was prominent in the liver, dependent on parasite burden and associated with an accumulation of functionally exhausted Th1 cells. These results highlight potential negative effects of combining different immune modulation strategies.